Schedule YPresented By-MANISH KUMAR SHARMA Presented To CENTER FOR CLINICAL RESEARCH SHARDA UNIVERSITY, GREATER NOIDA,UP6/6/2012

Outline of Presentation1. History 2. Drug and cosmetic Act,1940 and Schedules 3. What actually Schedule Y is ? 4. Old/New(amended) Schedule Y 5. Why Changes in Schedule Y ? 6. Rules under it 7. Divisions of Schedule Y

8. New Amendments 9. Conclusion

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Lets revise the History Drug and Cosmetic Act, 1940 was enacted(D/C

Act) Pharmacy Act , 1948 Drug and Magic Remedies Act, 1954 The Narcotic and Psychotropic Substance Act and Rules, 1985 Ethical guidelines for Biomedical Research on Human Participants,2000 by ICMR6/6/2012

Indian GCP Guidelines,2001 Amendments to Drug and Cosmetic

Act,2002 Revised Schedule Y, 2005 Guidelines for Pre Clinical Data for r-DNA Vaccines,2007

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Drug and Cosmetics Act,1940In 1940 D/C Act Was enacted in 1945 Drug Rules were Promulgated in December and enforcement Start in 1947 Now have been called as D/C Act Objective- To ensure that the drug is available to the People are safe and cosmetics marketed for safer use.

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Schedules to Rules, 1945Schedule A- Forms for marketing application for licenses, issue, and renewal B- Fee for test/analysis by CDL or SDL C/C1- talk about I/M/S/D of sera, vaccines D-List of drugs exempted from the provisions that are applicable to import of other drug E- Omitted , E1- list of poisonous substance under Ayurveda,Unani,Sidha system F- Production/testing/storage/packaging/labeling F1-biological preparations F2- SD F3- umbilical tapes G- List of drug used under medical supervision H- List of drug sold under Prescription I-Omitted J-Diseases may not cure/prevent by drugs K-List of drugs exempted from the provisions that are applicable to manufacture of other drug L-Omitted6/6/2012

M-GMP N-List of minimum equipment in Pharmacy O-Standards for disinfections P- Life period of drug Q-List of dyes/coloring agents in soap/cosmetics R-Standards for Mechanical contraceptives S-Standards for cosmetics T-GMP for A/U/S system of medicines U- Records for manufacturing/raw materials in drugs V- Standards for potent medicines X- List of drugs whose I/M/S are governed by special provision W- Omitted Y- About CT6/6/2012

Schedule Y The enforcement that came into existence in 1988 was an essential

provision for providing support to the upscale of generic pharma scenario present in those days. With the entry of large pharmaceutical companies along with the multiple multinationals in field of clinical research the needs changed and a revised version of Schedule Y in line with ICH-GCP (International Council of Harmonization and Good Clinical Practice) standard was put forth in 1995. Since then multiple revisions to Schedule Y took place to provide a healthy environment for clinical research to be conducted in India.

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Schedule Y

Its a Law not merely a Guideline6/6/2012

Schedule YSchedule Y ,the current regulator (of

CDSCO), enforced law in India has been established under Drug and Cosmetic Act,1945. The regulations to be followed when conducting Clinical Trial in India.

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contt..REQUIREMENTS AND GUIDELINES FOR PERMISSION TO IMPORT AND / OR MANUFACTURE OF NEW DRUGS FOR SALE OR TO UNDERTAKE CLINICAL TRIALS IN INDIA6/6/2012

Amended Schedule Y

Regulations and Guidelines for permission for development (preclinical and/or clinical), import and manufacture of New Drugs for Marketing in India DATE- 20TH JAN,20056/6/2012

Why Changes in Schedule Y To frame guidelines for the current scenario of Clinical

research. CDSCO and DTAB formulated GCP under Schedule Y in 2005. Schedule Y 1988 relevant to predominantly generic industry. GCP trials since 1995, and arrival of IPR regime in 2005. Integration of India in global clinical development and legal support to GCP guidelines. Improvements in quality of clinical trials. It has outlined extensive study criteria in line with the globally accepted formats such as ICH and US FDA guidelines.

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Rules under Schedule YRule Permission To Import New Drugs To manufacture New Drugs To import or manufacture fixed dose Combinations To conduct Clinical Trials for New Drug/Investigational New Drug Definition of Clinical Trial

122 A 122 B 122 D

122 DA

122DAA

122 E

Definition of New Drug

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Rule 122DA To conduct Clinical Trials

for New Drug/Investigational New DrugNew chemical entity or a product having therapeutic indication but which has never been earlier tested on human beings.

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122-E. 122-E. -Not been used in the country under labeling

conditions Approved but now proposed to be marketed with modified or new claims indications, dosage, dosage form , route of administration-FDC, individually approved, to be combined for the first time in a fixed ratio or if ratio is changed

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Old schedule Yin the older version there are only 5 appendices Appendix I: Declaration of Helsinki Appendix II: Schedule Y Appendix III: Format for submission of Pre-clinical and clinical data for r-DNA based vaccines, diagnostics and other biologicals. Appendix IV: Investigators Brochure Appendix V: Essential Documents

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Significant changesNew concept1)Clinical trials a) Definition of CT b) ICD New c) responsibilities of ethical committee- New d) PMS- New 2) Studies in special populations a) Geriatric b) Pediatrics c) Pregnant d) PMS - New e) BA/BE - New 3)Formats for critical documents6/6/2012

Older concept1.1 Nature of CT 1.2 Permission of CT 1.3 ICD but no details 1.4 Responsibilities of sponsor/investigator No PMS 2) Special Studies No Separation

Appendix I Data to be submitted along with the application to conduct clinical trials / import / manufacture of new drugs for marketing in the country.

a.

b.c. d.

e.f. g.

h.i. j.

Introduction about the drug Chemical and pharmaceutical information (e.g. Enatiometry) Animal pharmacology Animal toxicology Human /clinical pharmacology(Phase-I) Therapeutics exploratory(Phase-II) Therapeutics confirmatory(Phase-III) Special studies( paediatrics, pregnant) Regulatory status in other countries if available Prescribing information(drug labeling and prescribing inf.)6/6/2012

APPLICATION FOR PERMISSION UNDER FORM 44, REGULATORY AUTHORITIES, FEES AND TEST LICENCE

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Regulatory authoritiesMinistry of Chem & FertilizersMinistry of Health Health Secretary NPPA National Pharmaceutical Pricing Authority Pricing Regulations DGHS Director General of Health Services DCGI Drug Controller General of India CDRL/CDTL Gov. Drug Testing Laboratories State Drug Regulatory Authority :FDA DBT Department of Biotechnology Additional Secretary Ministry of Sci & Tech Ministry of Enviro

GEAC Genetic Engineering Approval Committee

PROCESSAPPLICATION FORM 44 -Imp FF -Imp Rm -Mfg FF -Mfg Rm -CT Approval Form 45 (IMP FF)

Approval Form 45 A (IMP RM)Approval Form 46 (MFG FF)

NOC FOR CT + Test Licence for Import

Application Form 46 A (MFG RM)

Fee according to Schedule Y Import ff/ Mfg ff/ Import bulk + Mfg ff

= Rs 50,000/-

of new drug Application by same applicant,

= Rs 15,000/-

for modified dosage form or with new claim Secondary applicants after 1

year of approval

= Rs 15,000/= Rs 15,000/-

Import / Mfg FDC Conduct Clinical trial with ND/IND

Phase I = Rs 50,000/Phase II = Rs 25,000/Phase III = Rs 25,000/No separate fee to be paid along with application for import / mfg based on successful completion

Appendix I-AData required to be submitted by an applicant for grant of permission to import &/or manufacture a new drug already approved in the country.

a) Introductionb) Chemical and pharmaceutical information c) Marketing information d) Special studies6/6/2012

Appendix III Animal toxicology (Non-clinical toxicity studies)1) SDTS- Minimum 5 animal, 24hr observation 2) DRS- On one Rodent Species 3) RDTS- a) 14 to 28 days- on 1 Rodent and 1 Non Rodent b)90 days- same as above but introduction of HIGH DOSE REVERSAL . 4) MFS- Rodent Species, Dose selection should be done on basis of 14 to 28 days studies. 5) FFS- should be carried out for all drugs( Appendix I- 4.4)

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Animal toxicology (Non-clinical toxicity studies)Other Studies a. Hypersensitivity b. Genotoxicity c. Carcinogenicity

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Appendix IV-Animal PharmacologyAnimal pharmacology studies are done to see the effect if IP on different systems like CVS CNS ANS RS US GIT

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Appendix V- INFORM CONSENT Trial involves research Purpose Trial treatments and randomization Trial procedures Risk Benefit Alternative treatments Compensation / treatment for injury Subjects responsibilities Experimental aspects Any payment6/6/2012

Essential Elements of Informed Consent Confidentiality New information Voluntary participation

Person/s to contact for study information Rights of subject, if study related injury Reasons for termination Duration of study Number of subjects Any other pertinent information6/6/2012

Format of Informed Consent Form Study Title

Subjects Initials e.g. Subjects Name/ Date of Birth / Age Consent Statements with initials in

Signature (or Thumb impression) of the Subject b) Legally Acceptable Representativea) Signature of the Investigator

Study Investigators Name Signature of the Witness Name of the Witness6/6/2012

Appendix VI- FDCsCombination therapy with two or more agents having complementary mechanisms of action is an example of incremental innovation that may extend the range of therapeutic options in the treatment of almost every human diseaseData requirements of Fixed Dose Combinations Fixed Dose combinations (FDC) fall into four groups and their data requirements accordingly. The first group of FDC includes those in which one or more of the active ingredients is a new drug. The second group of FDC includes those in which active ingredients already approved/marketed . The third group of FDC includes those which are already marketed The fourth group of FDC includes those whose individual active ingredients have been widely used.6/6/2012

Appendix VII Undertaking By The Investigator1) Full name, address and title of the Principal Investigator 2)

3) 4) 5) 6) 7)

Name and address of the medical college, hospital or other facility where the clinical trial will be conducted: Education, training &experience that qualify the Investigator for the clinical trial (Attach details including Medical Council registration number, and / any other statement of qualification Name and address of all clinical laboratory facilities to be used in the study. Name and address of the Ethics Committee ,responsible for approval and continuing review of the study. Names of the other members of the research team (Co- or sub-Investigators) who will be assisting the Investigator in the conduct of the investigation. Protocol Title and Study number (if any) of the clinical trial to be conducted by the Investigator. Signature with Date.

VII.2 Commitments by The InvestigatorStudy not to begin until EC / DCGI approval Adherence to protocol Personal supervision Ensure requirements of IC and EC review Report of AE to sponsor Understanding of investigators brochure Ensure that all associates, colleagues and employees suitably qualified and experienced and aware of their obligations h. Report all unexpected serious adverse events to the Sponsor in 24 hrs and EC within 7 days. i. Maintenance of records and availability for audits / sponsor inspection / EC and DCGI. Cooperation in auditsa. b. c. d. e. f. g.6/6/2012

Appendix VIII ETHICS COMMITTEE COMPOSITIONICH GCP At least 5 members. At least 1 member nonscientific area. Quorum members number not detailed. Maximum number is not detailed. Not recommended.

Indian GCPFairly small (5-7 members). 1 member from nonscientific area

Schedule-YAt least 7 members.

Not Explained. The quorum should have at least 5 The quorum should have a members. Maximum number is minimum of 5 members. not detailed. 12 to 15 is the maximum recommended number. Not recommended. Member Secretary belongs to the same Institution.

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Appendix IX- Stability testing of New DrugsStability testing is to be performed to provide evidence on how the quality of a drug substance or formulation varies with time under the influence of various environmental factors such asa. Temperature b. Humidity and c. Light Objective. - To establish shelf life for the formulation and recommended storage conditions.

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STABILITY TESTINGStress testing of the drug substance should be conducted to identifya. The degradation pathways b. Evaluate the intrinsic stability of the molecule and c. Validate the stability indicating power of the analytical procedures used. Stress testing may generality be carried out on a single batch of the drug substance. It should include the effect of-Temperature, humidity, oxidation, photolysis on the drug substance. TWO TYPES OF STUDY IS DONE 1)Long-term testing should cover a minimum of 12 months duration on at least three primary batches of the drug substance or the formulation at the time of submission6/6/2012

STABILITY TESTING2)Accelerated testing should cover a minimum of 6 months duration at the time of submission. Study conditions for drug substances and formulations intended to be stored under general conditions.

Study conditions and Duration of studyi)Long term 30C 2C/65% RH 5%RH 12 months ii)Accelerated 40C 2C/75% RH 5% RH 6 months If at any time during 6 months testing under the accelerated storage condition, such changes occur then further studies are done. NOTE- The nature of the stress testing will depend on the individual drug substance and the type of formulation involved.

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Title page Table of content a) a) introduction b) Study rationale c) Study design d) Study population e) Subject eligibility f) Study treatment g) AE h) Data analysis i) Undertaking by investigator

Appendix X Contents of the Proposed Protocol

NOTE- Protocol is assigned by sponsor after getting CDA from investigator6/6/2012

Appendix XI- Data Elements For Reporting SAE in a Clinical Triala) Patient details(Age, sex, weight, height)

b) Suspected drug( Generic name, DFD, ROA)c) Detail of SUSPECTED ADR( severity, start date, stop

date, hospitalization or not) d) Details about investigator

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New Amendments on 30.06.2009CLINICAL RESEARCH ORGANISATION REGISTRATION These guidelines have been approved by DTAB 1)Rule 122 DAB. Registration of clinical research organization for conducting clinical trials. The clinical research organisation, contracted in writing by the sponsor to carry out any or all obligations transferred to it by the sponsor, shall perform such functions only, if it is duly registered, under the rules, by the Licensing Authority defined in Clause (b) of Rule 21.6/6/2012

Schedule Y-1-Requirements and Guidelines for registration of clinical research organisations 2. Criteria for Registration(I) The Clinical Research Organisation shall be under the charge of a person who is responsible for the overall activities of the organisation. He shall be thoroughly familiar with the investigational product(s), the protocol, written informed consent forms or other information provided to the subjects, the standard operative procedures by the sponsors, GCP guidelines and other rules applicable to the conduct of clinical trials. (ii) The organisation shall have adequate resources, qualified and trained staff for oversight of clinical trials. The staff members are required to be trained regularly to update their skills.6/6/2012

(iii) The organisation shall ensure that the trials are adequately monitored and the trial related responsibilities transferred to it, partially or fully, by the sponsor are discharged effectively and efficiently. (iv) The organisation shall implement quality assurance and quality control as per standard operative procedures designed for the purpose. Such SOPs shall be well documented.

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New Amendments on 18th Nov.2011

1)Rule 122-DAB- compensation during injury or death during clinical trial In case of injury in clinical trial the compensation is based as per the recommendation of EC/IRB , it may be financial or medical. 2) In case of death his/her legal heirs are entitled for the financial compensation, subject to the confirmation to EC

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ConclusionWith the Schedule Y, efforts are aligned in a single direction to ensure that irrespective of the country, the data generated is of good quality and standard which can be accepted worldwide6/6/2012

ReferencesGupta S.K, Basic principles of Clinical research and Methodology, 2007.

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QUERIES????

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